title: Angiotensin II type 2 receptor correlates with therapeutic effects of losartan in rats with adjuvant-induced arthritis.
abstract: The angiotensin II type 1 receptor (AT1R) blocker losartan ameliorates rheumatoid arthritis (RA) in an experimental model. In RA, AT2R mainly opposes AT1R, but the mechanism by which this occurs still remains obscure. In the present study, we investigated the role of AT2R in the treatment of rats with adjuvant-induced arthritis (AIA) by losartan. Adjuvant-induced arthritis rats were treated with losartan (5, 10 and 15 mg/kg) and methotrexate (MTX; 0.5 mg/kg) in vivo from day 14 to day 28. Arthritis was evaluated by the arthritis index and histological examination. Angiotensin II, tumour necrosis factor-α, and VEGF levels were examined by ELISA. The expression of AT1R and AT2R was detected by western blot and immunohistochemistry analysis. After stimulation with interleukin-1β in vitro, the effects of the AT2R agonist CGP42112 (10(-8) -10(-5)  M) on the chemotaxis of monocytes induced by 10% foetal calf serum (FCS) were analysed by using Transwell assay. Subsequently, the therapeutic effects of CGP42112 (5, 10 and 20 μg/kg) were evaluated in vivo by intra-articular injection in AIA rats. After treatment with losartan, the down-regulation of AT1R expression and up-regulation of AT2R expression in the spleen and synovium of AIA rats correlated positively with reduction in the polyarthritis index. Treatment with CGP42112 inhibited the chemotaxis of AIA monocytes in vitro, possibly because of the up-regulation of AT2R expression. Intra-articular injection with CGP42112 (10 and 20 μg/kg) ameliorated the arthritis index and histological signs of arthritis. In summary, the present study strongly suggests that the up-regulation of AT2R might be an additional mechanism by which losartan exerts its therapeutic effects in AIA rats.
authors.affiliation: Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine of China Education Ministry, Hefei, Anhui Province, China.
authors.forename: Di
authors.initials: D
authors.lastname: Wang
authors.forename: Shanshan
authors.initials: S
authors.lastname: Hu
authors.forename: Jie
authors.initials: J
authors.lastname: Zhu
authors.forename: Jun
authors.initials: J
authors.lastname: Yuan
authors.forename: Jingjing
authors.initials: J
authors.lastname: Wu
authors.forename: Aiwu
authors.initials: A
authors.lastname: Zhou
authors.forename: Yujing
authors.initials: Y
authors.lastname: Wu
authors.forename: Wendi
authors.initials: W
authors.lastname: Zhao
authors.forename: Qiong
authors.initials: Q
authors.lastname: Huang
authors.forename: Yan
authors.initials: Y
authors.lastname: Chang
authors.forename: Qingtong
authors.initials: Q
authors.lastname: Wang
authors.forename: Wuyi
authors.initials: W
authors.lastname: Sun
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D000843:Ankle Joint / Q000187:drug effects / Q000473:pathology; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects; D007270:Injections, Intra-Articular; D019808:Losartan / Q000494:pharmacology* / Q000627:therapeutic use*; D008297:Male; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D009842:Oligopeptides; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D000804:Angiotensin II; C060894:CGP 42112A; D019808:Losartan
keywords: adjuvant-induced arthritis; angiotensin II type 2 receptor; losartan; rheumatoid arthritis